The establishment and maintenance of pregnancy requires the coordinated activity of a highly specialized maternal tissue, the decidua requires extensive endometrial ell proliferation, differentiation and severe regression and reorganization. The overall goal of this project is to examine the role of decidua-derived factors in the normal development of the decidua. The first specific aim is based on the recent finding of hyperproliferation and development of large decidua in the cyclin dependent kinase inhibitors (p21/p27) double knock-out and that of small decidua in the IL-11Ralpha deficient mice. The role of p21 and/or p27 in the cessation of decidual cell proliferation and initiation of differentiation and their inhibition by IL-11 will be investigated using the knock-out mice, decidual cells derived from these cells as well as two cell lines recently developed in our laboratory. We will tet the hypothesis that in the normal development of the decidua IL-11 inhibits the expression of p21/p27 and thus allows the cells to proliferate leading to normal sized decidua. We will also examine whether decidually derived TGFbeta is responsible for stimulation of p21 and/or p27 leading to inhibition of proliferation and stimulation of differentiation in the decidua. The goal of the second aim of this proposal is to examine the role of the endogenously produced activin A in the regression and reorganization of the decidua, to define the signalling mechanisms by which activin A causes cell death and to determine whether the apoptotic role of activin A in the decidua involves activin A regulation of both the expression and action of caspase 3. The third aim of this proposal is based on our finding that rat decidual PRL may regulate and direct the expression of activin A and inhibits apoptosis in the decidua. We will examine the signaling mechanism by which PRL prevents activin A expression and will examine whether PRL regulates the transcriptional activity of the activin A gene through the PKB/Forkhead pathway. We will also explore the possibility, using the PRL knock-out mice, whether PRL prevention of decidual apoptosis in due to inhibition of decidual activin A.